Inhibition of HDAC3 induces neuroprotection by activating the Npas4 signaling pathway following surgical brain injury in rats

TL;DR

Inhibiting HDAC3 protects the brain after injury in rats by boosting Npas4, which helps reduce swelling and inflammation.

Contribution

This study reveals that HDAC3 inhibition promotes neuroprotection in early surgical brain injury via Npas4 activation.

Findings

HDAC3 protein expression increases after surgical brain injury in rats.

RGFP966, an HDAC3 inhibitor, reduces brain edema and inflammation while enhancing autophagy.

HDAC3 inhibition up-regulates Npas4, contributing to neuroprotection in early brain injury.

Abstract

Histone deacetylase 3 (HDAC3) can acetylate histones, negatively regulating Neuronal Per-Arnt-Sim domain protein 4 (Npas4) and participating in various pathological processes of central nervous system lesions. However, the role of HDAC3 in early surgical brain injury (SBI) remains elusive. This study aimed to determine the role of HDAC3 in early rat SBI and its underlying mechanism.

The SBI model was constructed using the right frontal lobotomy of adult male Sprague-Dawley rats. The effects of RGFP966, a specific HDAC3 inhibitor, were assessed by western blotting, immunofluorescence, neurological scoring, and fluoro-Jade C staining.

HDAC3 protein expression was up-regulated after SBI and peaked at 24 hr relative to the Sham group. RGFP966 application can significantly improve brain edema and neurological dysfunction 24 hr after SBI, enhance autophagy, and reduce inflammation. In addition, we observed that Npas4 expression increased in SBI rats and was further up-regulated after HDAC3 inhibition.

HDAC3 plays a role in rats’ complex pathogenesis of SBI. HDAC3 inhibition imparts a protective role in early brain injury in SBI in rats by regulating autophagy and inflammation via up-regulation of Npas4.

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